DIVA: Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers

Sponsor

Professor Francine Ducharme (Other)

Overall Status

Recruiting

CT.gov ID

NCT03365687

Collaborator

Canadian Institutes of Health Research (CIHR) (Other), EURO-PHARM International Canada, Inc. (Other)

865

Enrollment

Locations

Arms

Anticipated Duration (Months)

108.1

Patients Per Site

1.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In this 7-month randomized controlled trial, children aged 1 to less than 6 years, with recurrent asthma attacks triggered mostly by colds, will receive a high dose of vitamin D or a placebo every 3.5 months during their usual clinic visit, and a daily supplement of vitamin D or a placebo. This study will test whether children in vitamin D group have less frequent and less severe asthma exacerbations compared with those receiving placebo.The study will also document the safety profile of this strategy.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Dietary Supplement: Vitamin D Dietary Supplement: Placebo	Phase 3

Detailed Description

This is a multicenter triple-blind randomized parallel-group, placebo-controlled trial of vitamin D3 supplementation. Children aged 1-5 (<6) years with physician-diagnosed asthma predominantly triggered by upper respiratory tract infection will be screened for enrolment in paediatric asthma, respiratory or allergy clinics and the ED departments and randomized between Sept 1 to January 31, annually (4 recruitment years).

Using a computer-generated random list, stratified by site, children will be allocated (1:1) using permuted block randomisation method to enhance concealment.

Children will be followed for 7 months, with 3 visits every 3.5 months with repeated urine (for calcium:creatinine ratio) and blood samples. In addition, ten (10) days after each bolus, urine will be sampled for urinary calcium:creatinine ratio. In case of elevated urine calcium:creatinine ratio, a blood sample may be needed primarily for markers of calcium metabolism and exploratory outcomes. Only patients enrolled at CHU Sainte-Justine and Montreal Children's Hospital will receive a systematic home visit 10 days after first bolus for both urine and blood samples. There will be 6 follow-up phone calls, at week 1 and then monthly, to inquire about exacerbations and URTIs, remind parents to complete questionnaires and to collect a nasal swab at each exacerbation and screen for adverse events.

The main outcome is the number of courses of rescue oral corticosteroids (OCS) per child during the study period. Several secondary outcomes will be documented using biological samples and validated questionnaires to ascertain laboratory-confirmed respiratory infections, intensity and severity of exacerbations, mean number of ED visits, parents' functional status during exacerbations, de-intensification of preventive asthma therapy, cost effectiveness, and safety profile.

A sample of 432 children (400+7,5% attrition) per arm will provide 80% power with a two-tailed alpha of 5% to detect a 25% relative reduction in the mean number of exacerbations requiring OCS per child.

An intention-to-treat (ITT) analysis will be carried out with all randomised children.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

865 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation.This is a randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

The manufacturer, Europharm, will provide the active vitamin D3 and placebo preparations, identical in appearance and taste, in coded latex-free bottles. A web-based randomisation system will allow Site pharmacies to obtain allocated treatment number, prepare the 2 mL bolus in coded syringes and the coded bottles containing the daily dose, and dispense study drugs in masked kits.

Primary Purpose:

Prevention

Official Title:

Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers: a Randomized Controlled Multicenter Trial (DIVA)

Actual Study Start Date :

Oct 1, 2018

Anticipated Primary Completion Date :

Jul 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Vitamin D Vitamin D supplement (100,000 IU) orally at baseline and at 3.5 months with daily 400 IU vitamin D for 7 months	Dietary Supplement: Vitamin D 2 mL of 50,000 IU/mL at baseline and at 3.5 months with a daily dose of 1 mL (400 IU/mL) for 7 months Other Names: Cholecalciferol
Placebo Comparator: Placebo Placebo orally at baseline and at 3.5 months with daily placebo during 7 months	Dietary Supplement: Placebo 2 mL of placebo at baseline and at 3.5 months with a daily dose of placebo (1 mL) for 7 months

Arm

Intervention/Treatment

Active Comparator: Vitamin D

Vitamin D supplement (100,000 IU) orally at baseline and at 3.5 months with daily 400 IU vitamin D for 7 months

Dietary Supplement: Vitamin D

2 mL of 50,000 IU/mL at baseline and at 3.5 months with a daily dose of 1 mL (400 IU/mL) for 7 months

Other Names:

Cholecalciferol

Placebo Comparator: Placebo

Placebo orally at baseline and at 3.5 months with daily placebo during 7 months

Dietary Supplement: Placebo

2 mL of placebo at baseline and at 3.5 months with a daily dose of placebo (1 mL) for 7 months

Outcome Measures

Primary Outcome Measures

Number of asthma exacerbations per child treated with rescue oral corticosteroids [7 months]
Group difference in the mean number of exacerbations treated with rescue oral corticosteroids/child

Secondary Outcome Measures

Laboratory-confirmed respiratory infections [7 months]
Group difference in mean number of laboratory-confirmed respiratory infections during asthma exacerbations
Severity of asthma symptoms during asthma exacerbations [7 months]
Group difference in the mean severity of asthma symptoms documented on the 'Asthma Flare-up Diary for Young Children'
Duration of asthma symptoms during asthma exacerbations [7 months]
Group difference in the mean duration of asthma symptoms documented on the validated 'Asthma Flare-up Diary for Young Children'
Intensity of use of rescue β2-agonists during asthma exacerbations [7 months]
Group difference in the mean cumulative use of rescue β2-agonists during exacerbations documented on the validated 'Asthma Flare-up Diary for Young Children'
Parents' functional status during asthma exacerbations [7 months]
Group difference in the mean parents' functional status during exacerbation as documented on the validated 'Effect of a child's asthma flare-up on parents questionnaire'
Mean number of ED visits for asthma exacerbations [7 months]
Group difference in mean number of ED visits for asthma exacerbations
De-intensification of preventive asthma therapy [7 months]
Group difference in proportion of children with de-intensification of preventive asthma therapy
Intervention cost-effectiveness [7 months]
Cost of intervention vs. cost (family expenses and health care) of exacerbations

Other Outcome Measures

Hypercalciuria [7 months]
Group difference in the proportion of children with ≥1 occurrence of hypercalciuria (urinary calcium: creatinine ratio >1.38 mmol/mmol for children aged 1-<2 years, or >1.1 mmol/mmol for children aged 2-<5 years, or >0.77 mmol/mmol for children aged ≥5 years)
Hypercalcemia [7 months]
Group difference in the proportion of children with clinically significant hypercalcemia (>2.63 mmol/L)
Elevated serum 25-hydroxyvitamin D [7 months]
Group difference in the proportion of children with ≥1 occurrence of elevated serum 25OHD (greater than 250 nmol/L)
Adverse Health Events [7 months]
Group difference in the distribution of adverse health events
Gene expression [3.5 months]
Group difference in the change in gene expression levels (between baseline and 3.5 months) in blood peripherical mononuclear cells, adjusted for cell distribution estimated from lymphocyte differentiation in a subset of patients

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 5 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 1-5 years
Physician-diagnosed asthma (as per the 2015 Canadian Position Paper on the diagnosis of preschool asthma)
≥1 asthma exacerbation requiring rescue oral corticosteroids (OCS) in the past 6 months or ≥2 in the past 12 months (as documented by pharmacy/medical records)
≥4 upper respiratory tract infections (URTIs) in the past 12 months (as per parental report)
URTIs as the main asthma trigger (as per parental report)

Exclusion Criteria:

Intake > 400 IU/day of vitamin D3 supplements or fish oil in the past 3 months
Intention to use > 400 IU/day of vitamin D3 supplements or fish oil in the fall and winter
Extreme prematurity (< 28 week gestation)
No vitamin D supplementation (if breast-fed in the last 6 months)
Vitamin D restrictive diets, that is, minimal intake of vitamin D fortified milk (<250 mL/day for 1-3 years or <375 mL/day for 4-6 years AND no other (or <200 IU/day) vitamin D supplement
Recent immigrants from regions at high risk of rickets (in the past 12 months)
Recent refugees (in the past 12 months)
Undernourished children
Other chronic respiratory disease (e.g. Cystic fibrosis, Bronchopulmonary dysplasia) or chronic kidney, gastrointestinal, endocrinological or cardiac diseases, or sickle cell anemia?
History of bone disorder disease (e.g. rickets, osteomalacia)
Intake of oral anti-epileptic, diuretic or anti-fungal medications
Anticipated difficulty with follow-up or with adherence to the intervention or the procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
2	Children's Hospital of London Health Sciences Centre	London	Ontario	Canada	N6A 2V5
3	Children's Hospital of Eastern Ontario	Ottawa	Ontario	Canada	K1H 8L1
4	Montreal Children's Hospital	Montreal	Quebec	Canada	H3H 1P3
5	CHU Sainte Justine	Montreal	Quebec	Canada	H3T1C5
6	Maisonneuve-Rosemont Hospital	Montreal	Quebec	Canada
7	CHU de Québec-Université Laval	Québec	Quebec	Canada	G1V 4G2
8	CHU de Sherbrooke	Sherbrooke	Quebec	Canada	J1G 2E8